Specific Aim (SA)1. To clinically target the DNA repair and cell cycle checkpoint pathways in HRD- women's cancer. During FY2016, we have completed patients accrual and translational endpoints analysis for the phase 1 olaparib/carboplatin study triple negative breast cancer (TNBC) cohort (08-C-0092) and for the PK/PD study of olaparib/carboplatin (11-C-0022). We previously reported intermittent administration of olaparib with carboplatin yields clinical benefit in women with germline BRCA mutation-associated ovarian or breast cancer. Our findings show this combination also has activity outside of BRCA mutation-associated cancers and that carboplatin pre-exposure increases olaparib clearance due to intracellular olaparib accumulation, suggesting carboplatin should be administered prior to olaparib, and support evaluation of the combination more broadly in women's cancer patients. Manuscripts detailing clinical and correlative studies of these two studies are submitted for publication. Another approach to modulate DNA repair activity in HRD-women's cancers is to interfere with cell cycle checkpoint pathways. ATR and its downstream kinase CHK1, arrest cell cycle progression allowing time for DNA repair. ATR/CHK1 blockade inhibits cell cycle arrest, resulting in progressive DNA damage and ultimately apoptosis. Consistent with this, we have observed single agent activity (a response rate of 36%) of prexasertib (LY2606368), a second generation CHK1/2 inhibitor, in heavily pretreated recurrent BRCA wild type HGSOC patients from an ongoing phase 2 investigator-initiated study (14-C-0156). This newly uncovered clinical activity will be reported as oral presentation at 2016 ESMO and discussions for any new clinical trials including prexasertib (LY2606368) are currently ongoing with Eli Lilly. This phase 2 study incorporates tumor biopsies and blood collections, genomic analyses and other molecular investigations to identify mechanisms of sensitivity or resistance, and to better define the subsets that respond to therapy, which have not clinically been examined in HRD-women's cancer. In addition, a phase 2 investigator-initiated study will examine clinical synergy of the ATR inhibitor (AZD6738) and PARPi in recurrent ovarian cancer with biomarkers analysis. The concept was approved by a CCR Scientific Review Committee and the protocol is being developed, with anticipated opening in 1Q 2017. My lab efforts are aimed at preclinical investigation of agents that target the DNA repair and related pathways and at characterizing biomarkers that predict response to these agents from tumor biopsies. Currently, my group is examining the potential synergy of PARPi with CHK1/2 inhibition or with anti-apoptotic pathway inhibition preclinically in germline BRCA mutation -associated ovarian cancer and HGSOC cells. Preliminary in vitro work on PARPi and LY2606368 combination was presented at 2016 AACR. These preclinical studies will allow me to query the genomic and proteomic composition of the HGSOC cells, and patients' tumors, before and after treatment, to identify the biomarkers that predict response. These preclinical projects also will provide the ability to move rapidly into the hypothesis-driven clinical trials of the combination of the different pathway regulators in recurrent HGSOC. SA2. To investigate efficacy of PARPi and VEGFR1-3 inhibition compared to standard of care therapy in platinum-resistant recurrent ovarian cancer patients. I have expanded my HRD-women's cancer clinical program, and have developed and opened the new phase 2/3 multi-center international trial during FY2016. Our group has initiated preclinical work demonstrating in vitro synergy between a VEGFR1-3 inhibitor, cediranib and a PARPi, olaparib. We then joined a multi-institutional randomized phase 2 study comparing the combination of cediranib/olaparib to olaparib alone in women with recurrent platinum-sensitive ovarian cancer as a translational lead site. Significant evidence of activity of cediranib/olaparib combination from this phase 2 study led to develop the phase 3 international trials through NRG (NSABP-RTOG-GOG) Oncology. I am a PI of the phase 2/3 study comparing the combination of cediranib/olaparib against each agent alone and standard chemotherapy in platinum-resistant ovarian cancer. The results of this trial could potentially produce practice-changing results, given that limited data of targeted-therapy in platinum-resistant recurrent patient population. The correlative studies will be done through NRG Oncology in collaboration with Dr. E Swisher (Univ. of Washington), Dr. D Levine (NYU), Dr. A Nixon (Duke), and J Trepel (NCI). Our goal is to identify potential predictive biomarkers that could be utilized to direct targeted therapy. This study is now enrolling the patients in U.S. and will open in Canada, Korea and Japan in 4Q 2016. SA3. To examine clinical synergy of immune checkpoint inhibition in combination with PARPi or angiogenesis inhibition in recurrent HRD-women's cancer with biomarkers analysis. The major challenges to immune checkpoint blockade strategy include the limited activity of single-agent immunotherapy and the lack of reliable biomarkers to predict patient response. I have developed and opened an investigator-initiated phase 1/2 study of a PD-L1 inhibitor, durvalumab (MEDI4736) in combination with olaparib or cediranib (15-C-0145). This study introduces the innovative concept of modulation of immune checkpoint activity with active targeted therapies in recurrent ovarian cancer. Our findings on safety and preliminary clinical activity of the two combination therapies were reported at 2016 ASCO. Our data suggest durvalumab and olaparib is safe and clinically active in combination in ovarian and TNBC patients without germline BRCA mutation. We noted durvalumab increases cediranib exposure (AUC and Cmax) when cediranib is given daily and we are now testing cediranib intermittent schedule (5 days on/2 days off). Phase 2 expansion studies of durvalumab with olaparib are now enrolling the patients for ovarian, TNBC, prostate and lung cancer cohorts. The correlative endpoints built into this study will further our understanding of the immune modulation by targeted agents and therapeutic susceptibility to the two different combinations. This project will provide initial findings to justify combination therapies using the PD-1/PD-L1 pathway inhibition and other small molecule targeted agents in recurrent HRD- cancer. This work was recently recognized by Lasker Clinical Research Scholar Program award, as part of a joint program between the Lasker foundation and NIH. Collectively, this focused clinical and translational approach will make our women's malignancies branch/CCR a recognized center focusing on the treatment of women with genetically high-risk breast and/or ovarian cancer, or those with tumor HRD phenotypes with a strong translational research program.